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Human Molecular Genetics Advance Access published online on October 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi394
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 2, 2005
Revised October 13, 2005
Accepted October 13, 2005

Article

Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells

Dolores Garcia Arocena 1, Christine K. Iwahashi 2, Nelly Won 2, Alexandra Beilina 2, Anna L. Ludwig 2, Flora Tassone 2, Philip H. Schwartz 3, and Paul J. Hagerman 4*

1 Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis, CA 95616 USA; Departamento de Genetica, Facultad de Medicina, UDELAR, Montevideo, Uruguay
2 Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis, CA 95616 USA
3 Children's Hospital of Orange County Research Institute, Orange, CA 92868 USA
4 Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, One Shields Avenue, Davis, CA USA

* To whom correspondence should be addressed.
Paul J. Hagerman, E-mail: pjhagerman{at}ucdavis.edu


  Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects some adult carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is thought to be caused by a toxic "gain-of-function" of the expanded-CGG-repeat FMR1 mRNA, which is found in the neuronal and astrocytic intranuclear inclusions associated with the disorder. Using a reporter construct with a FMR1 5' untranslated region harboring an expanded (premutation) CGG repeat, we have demonstrated that intranuclear inclusions can be formed in both primary neural progenitor cells and established neural cell lines. As with the inclusions found in post-mortem tissue, the inclusions induced by the expanded CGG repeat are {alpha}B-crystallin-positive; however, inclusions in culture are not associated with ubiquitin, indicating that incorporation of ubiquitinated proteins is a later event in the disease process. The absence of ubiquitinated proteins also argues against a model in which inclusion formation is due to a failure of the proteasomal degradative machinery. The presence of the expanded CGG repeat, as RNA, results in reduced cell viability as well as the disruption of the normal architecture of lamin A/C within the nucleus. This last observation, and the findings that lamin A/C is present in both the inclusions of FXTAS patients and the inclusions in cell culture, suggests that lamin A/C dysregulation may be a component of the pathogenesis of FXTAS; in particular, the Charcot-Marie-Tooth-type neuropathy associated with FXTAS may represent a functional laminopathy.


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